TNNI3
Troponin I, cardiac muscle is a protein that in humans is encoded by the TNNI3 gene.[5][6] It is a tissue-specific subtype of troponin I, which in turn is a part of the troponin complex.
The TNNI3 gene encoding cardiac troponin I (cTnI) is located at 19q13.4 in the human chromosomal genome. Human cTnI is a 24 kDa protein consisting of 210 amino acids with isoelectric point (pI) of 9.87. cTnI is exclusively expressed in adult cardiac muscle.[7][8]
Gene evolution
![](http://upload.wikimedia.org/wikipedia/commons/thumb/4/49/7-27_cTnI_align.jpg/220px-7-27_cTnI_align.jpg)
cTnI has diverged from the skeletal muscle isoforms of TnI (slow TnI and fast TnI) mainly with a unique N-terminal extension. The amino acid sequence of cTnI is strongly conserved among mammalian species (Fig. 1). On the other hand, the N-terminal extension of cTnI has significantly different structures among mammal, amphibian and fish.[8]
Tissue distribution
TNNI3 is expressed as a heart specific gene.[8] Early embryonic heart expresses solely slow skeletal muscle TnI. cTnI begins to express in mouse heart at approximately embryonic day 10, and the level gradually increases to one-half of the total amount of TnI in the cardiac muscle at birth.[9] cTnI completely replaces slow TnI in the mouse heart approximately 14 days after birth [10]
Protein structure
Based on in vitro structure-function relationship studies, the structure of cTnI can be divided into six functional segments:[11] a) a cardiac-specific N-terminal extension (residue 1–30) that is not present in fast TnI and slow TnI; b) an N-terminal region (residue 42–79) that binds the C domain of TnC; c) a TnT-binding region (residue 80–136); d) the inhibitory peptide (residue 128–147) that interacts with TnC and actin–tropomyosin; e) the switch or triggering region (residue 148–163) that binds the N domain of TnC; and f) the C-terminal mobile domain (residue 164–210) that binds actin–tropomyosin and is the most conserved segment highly similar among isoforms and across species. Partially crystal structure of human troponin has been determined.[12]
Posttranslational modifications
- Phosphorylation: cTnI was the first sarcomeric protein identified to be a substrate of PKA.[13] Phosphorylation of cTnI at Ser23/Ser24 under adrenergic stimulation enhances relaxation of cardiac muscle, which is critical to cardiac function especially at fast heart rate. Whereas PKA phosphorylation of Ser23/Ser24 decreases myofilament Ca2+ sensitivity and increases relaxation, phosphorylation of Ser42/Ser44 by PKC increases Ca2+ sensitivity and decreases cardiac muscle relaxation.[14] Ser5/Ser6, Tyr26, Thr31, Ser39, Thr51, Ser77, Thr78, Thr129, Thr143 and Ser150 are also phosphorylation sites in human cTnI.[15]
- O-linked GlcNAc modification: Studies on isolated cardiomyocytes found increased levels of O-GlcNAcylation of cardiac proteins in hearts with diabetic dysfunction.[16] Mass spectrometry identified Ser150 of mouse cTnI as an O-GlcNAcylation site, suggesting a potential role in regulating myocardial contractility.
- C-terminal truncation: The C-terminal end segment is the most conserved region of TnI.[17] As an allosteric structure regulated by Ca2+ in the troponin complex,[17][18][19] it binds and stabilizes the position of tropomyosin in low Ca2+ state[18][20] implicating a role in the inhibition of actomyosin ATPase. A deletion of the C-terminal 19 amino acids was found during myocardial ischemia-reperfusion injury in Langendorff perfused rat hearts.[21] It was also seen in myocardial stunning in coronary bypass patients.[22] Over-expression of the C-terminal truncated cardiac TnI (cTnI1-192) in transgenic mouse heart resulted in a phenotype of myocardial stunning with systolic and diastolic dysfunctions.[23] Replacement of intact cTnI with cTnT1-192 in myofibrils and cardiomyocytes did not affect maximal tension development but decreased the rates of force redevelopment and relaxation.[24]
- Restrictive N-terminal truncation: The approximately 30 amino acids N-terminal extension of cTnI is an adult heart-specific structure.[25][26] The N-terminal extension contains the PKA phosphorylation sites Ser23/Ser24 and plays a role in modulating the overall molecular conformation and function of cTnI.[27] A restrictive N-terminal truncation of cTnI occurs at low levels in normal hearts of all vertebrate species examined including human and significantly increases in adaptation to hemodynamic stress[28] and Gsα deficiency-caused failing mouse hearts.[29] Distinct from the harmful C-terminal truncation, the restrictive N-terminal truncation of cTnI selectively removing the adult heart specific extension forms a regulatory mechanism in cardiac adaptation to physiological and pathological stress conditions.[30]
Pathologic mutations
Multiple mutations in cTnI have been found to cause cardiomyopathies.[31][32] cTnI mutations account for approximately 5% of familial hypertrophic cardiomyopathy cases and to date, more than 20 myopathic mutations of cTnI have been characterized.[15]
Clinical implications
The half-life of cTnI in adult cardiomyocytes is estimated to be ~3.2 days and there is a pool of unassembled cardiac TnI in the cytoplasm.[33] Cardiac TnI is exclusively expressed in the myocardium and is thus a highly specific diagnostic marker for cardiac muscle injuries, and cTnI has been universally used as indicator for myocardial infarction.[34] An increased level of serum cTnI also independently predicts poor prognosis of critically ill patients in the absence of acute coronary syndrome.[35][36]
Notes
The 2015 version of this article was updated by an external expert under a dual publication model. The corresponding academic peer reviewed article was published in Gene and can be cited as: "TNNI1, TNNI2 and TNNI3: Evolution, regulation, and protein structure-function relationships". Gene. 576 (1 Pt 3): 385–394. 22 October 2015. doi:10.1016/J.GENE.2015.10.052. PMC 5798203. PMID 26526134. {{cite journal}} : Unknown parameter |authors= ignored (help) |
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Further reading
- Ni CY (2002). "Cardiac troponin I: a biomarker for detection and risk stratification of minor myocardial damage". Clinical Laboratory. 47 (9–10): 483–92. PMID 11596911.
- Hunkeler NM, Kullman J, Murphy AM (Nov 1991). "Troponin I isoform expression in human heart". Circulation Research. 69 (5): 1409–14. doi:10.1161/01.res.69.5.1409. PMID 1934363.
- MacGeoch C, Barton PJ, Vallins WJ, Bhavsar P, Spurr NK (Nov 1991). "The human cardiac troponin I locus: assignment to chromosome 19p13.2-19q13.2". Human Genetics. 88 (1): 101–4. doi:10.1007/BF00204938. PMID 1959915.
- Vallins WJ, Brand NJ, Dabhade N, Butler-Browne G, Yacoub MH, Barton PJ (Sep 1990). "Molecular cloning of human cardiac troponin I using polymerase chain reaction". FEBS Letters. 270 (1–2): 57–61. doi:10.1016/0014-5793(90)81234-F. PMID 2226790.
- Mittmann K, Jaquet K, Heilmeyer LM (Oct 1990). "A common motif of two adjacent phosphoserines in bovine, rabbit and human cardiac troponin I". FEBS Letters. 273 (1–2): 41–5. doi:10.1016/0014-5793(90)81046-Q. PMID 2226863.
- Noland TA, Raynor RL, Kuo JF (Dec 1989). "Identification of sites phosphorylated in bovine cardiac troponin I and troponin T by protein kinase C and comparative substrate activity of synthetic peptides containing the phosphorylation sites". The Journal of Biological Chemistry. 264 (34): 20778–85. PMID 2584239.
- Maruyama K, Sugano S (Jan 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
- Armour KL, Harris WJ, Tempest PR (Sep 1993). "Cloning and expression in Escherichia coli of the cDNA encoding human cardiac troponin I". Gene. 131 (2): 287–92. doi:10.1016/0378-1119(93)90308-P. PMID 8406024.
- Bhavsar PK, Brand NJ, Yacoub MH, Barton PJ (Jul 1996). "Isolation and characterization of the human cardiac troponin I gene (TNNI3)". Genomics. 35 (1): 11–23. doi:10.1006/geno.1996.0317. PMID 8661099.
- Jideama NM, Noland TA, Raynor RL, Blobe GC, Fabbro D, Kazanietz MG, Blumberg PM, Hannun YA, Kuo JF (Sep 1996). "Phosphorylation specificities of protein kinase C isozymes for bovine cardiac troponin I and troponin T and sites within these proteins and regulation of myofilament properties". The Journal of Biological Chemistry. 271 (38): 23277–83. doi:10.1074/jbc.271.38.23277. PMID 8798526.
{{cite journal}}
: CS1 maint: unflagged free DOI (link) - Takeda S, Kobayashi T, Taniguchi H, Hayashi H, Maéda Y (Jun 1997). "Structural and functional domains of the troponin complex revealed by limited digestion". European Journal of Biochemistry / FEBS. 246 (3): 611–7. doi:10.1111/j.1432-1033.1997.00611.x. PMID 9219516.
- Keane NE, Quirk PG, Gao Y, Patchell VB, Perry SV, Levine BA (Sep 1997). "The ordered phosphorylation of cardiac troponin I by the cAMP-dependent protein kinase--structural consequences and functional implications". European Journal of Biochemistry / FEBS. 248 (2): 329–37. doi:10.1111/j.1432-1033.1997.00329.x. PMID 9346285.
- Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (Oct 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
- Vassylyev DG, Takeda S, Wakatsuki S, Maeda K, Maéda Y (Apr 1998). "Crystal structure of troponin C in complex with troponin I fragment at 2.3-A resolution". Proceedings of the National Academy of Sciences of the United States of America. 95 (9): 4847–52. doi:10.1073/pnas.95.9.4847. PMC 20176. PMID 9560191.
- Barton PJ, Cullen ME, Townsend PJ, Brand NJ, Mullen AJ, Norman DA, Bhavsar PK, Yacoub MH (Apr 1999). "Close physical linkage of human troponin genes: organization, sequence, and expression of the locus encoding cardiac troponin I and slow skeletal troponin T". Genomics. 57 (1): 102–9. doi:10.1006/geno.1998.5702. PMID 10191089.
- Li MX, Spyracopoulos L, Sykes BD (Jun 1999). "Binding of cardiac troponin-I147-163 induces a structural opening in human cardiac troponin-C". Biochemistry. 38 (26): 8289–98. doi:10.1021/bi9901679. PMID 10387074.
- Redwood C, Lohmann K, Bing W, Esposito GM, Elliott K, Abdulrazzak H, Knott A, Purcell I, Marston S, Watkins H (Jun 2000). "Investigation of a truncated cardiac troponin T that causes familial hypertrophic cardiomyopathy: Ca(2+) regulatory properties of reconstituted thin filaments depend on the ratio of mutant to wild-type protein". Circulation Research. 86 (11): 1146–52. doi:10.1161/01.res.86.11.1146. PMID 10850966.
- Ward DG, Ashton PR, Trayer HR, Trayer IP (Jan 2001). "Additional PKA phosphorylation sites in human cardiac troponin I". European Journal of Biochemistry / FEBS. 268 (1): 179–85. doi:10.1046/j.1432-1327.2001.01871.x. PMID 11121119.